Consumption of ethanol (Et) alters certain regulatory aspects of the hypothalamic-pituitary-adrenal axis (HPAA). Because the integrity of this system depends on the coordinated synthesis and secretion of specific regulatory substances at the hypothalamic (e.g., corticotropin- releasing hormone (CRH); vasopressin (AVP); biogenic amines), pituitary- gland (e.g., beta-endorphin; ACTH) and adrenal gland (e.g., catecholamines; glucocorticoids) level, we have been evaluating the impact of Et at each level of the HPAA. Activation of the HPAA or hypercortisolism accompanies both short- and long-term consumption of Et and the Et withdrawal syndrome. Alcoholics often present with a pseudo- Cushing's syndrome in which some 17-40 percent of alcoholics do not respond to the dexamethasone suppression test during the first week of abstinence. Since a relative state of elevated glucocorticoids (chronic continuous or chronic intermittent) can lead to neural changes and even cell death, particularly in the hippocampus, the progressive loss of cognitive capacity in many alcoholics may indeed be due in part to hypercortisolemia and subsequent irreversible neural damage in the hippocampus and other areas of the central nervous system. Using an intragastric cannulated rodent model and short-term (4 days) intermittent alcohol administration, we have demonstrated site-specific CNS neurodegeneration in the dentate gyrus of the hippocampus, the entorherial cortex and the piriform cortex. Assessment of the role of increased glutamatergic neurotransmission, Ca++ uptake and levels of glucocorticoids in the observed neurodegeneration continues with hormonal and pharmacological replacement therapy. This project was formerly titled "Stress Axis, Immune System-Derived Cytokines and Ethanol."